tbuckley/cabot-search huggingface dataset:
Abstract 6391: Development of a novel strategy for cancer immunotherapy based on tumor immunogenicity improvement by HLA-drug interaction
Authors: Takeshi Susukida, So-ichiro Sasaki, Tomohiro Shirayanagi, Shigeki Aoki, Kousei Ito, Yoshihiro Hayakawa
Journal: Cancer Research (2023)

Abstract [Purpose] Tumors with low T cell infiltrates (poor immunogenicity) display lower probability of clinical response to immune checkpoint inhibitors. To achieve higher immunotherapy efficacy, it is imperative to establish a novel strategy for improving immunogenicity. Abacavir (ABC), an anti-HIV drug, binds to the specific allele of human leukocyte antigen (HLA-B*57:01) and activate CD8+ T cells by presenting altered abnormal peptides. In this study, we considered the immune interaction between ABC and HLA-B*57:01 improving immunogenicity in poorly immunogenic tumors leading to a potent anti-cancer effect. [Methods] Mice were inoculated subcutaneously with tumor cells into the right flanks and interperitoneally treated with either ABC 5 mg or vehicle (water) for consecutive 9 days (B16F10) or 13 days (3LL) after tumor inoculation. Each tumor size was measured using vernier calipers on every 2 days. Activation, proliferation, and IFN-γ secretion of tumor infiltrating CD8+ T cells were analyzed by FACS. [Results and Discussion] ABC treatment showed significant tumor growth inhibition associated with CD8+ T cell infiltration into tumor in mice inoculated with HLA-B*57:01 expressing B16F10 melanoma or Lewis lung carcinoma (3LL) cells, but neither in HLA-B*57:03 (negative allele)-expressing nor control tumors inoculated mice. Moreover, the tumor infiltrating CD8+ T cell were immune-activated and proliferated, with secreting IFN-γ. In contrast, ABC-induced anti-tumor effect was abrogated in CD8+ T cell-depleted mice, IFN-γ KO mice, and CXCR3-blocked mice. The combination therapy with anti-PD-1 antibody treatment induced better inhibition of tumor growth than ABC monotherapy in HLA-B*57:01 expressing B16F10 inoculated mice. These results suggested that ABC/HLA-B*57:01 interaction could improve tumor immunogenicity associated with CD8+ T cell-mediated anti-tumor effect in poorly immunogenic tumors. This finding lays a foundation to develop a novel drug-induced cancer immunotherapy targeting immune resistant tumors. Citation Format: Takeshi Susukida, So-ichiro Sasaki, Tomohiro Shirayanagi, Shigeki Aoki, Kousei Ito, Yoshihiro Hayakawa. Development of a novel strategy for cancer immunotherapy based on tumor immunogenicity improvement by HLA-drug interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6391.
Abstract 6388: High dose acetaminophen with n-acetylcysteine rescue inhibits M2 polarization of tumor associated macrophages
Authors: Alexander Neuwelt, Allyn Bryan, Won Lee, Pavani Pingali, Howard Li, Bhaumik Patel
Journal: Cancer Research (2023)

Abstract Background: High dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue is among the few treatments that has shown a signal of activity in phase I trials (21% response rate, 3/14 assessable patients) without achieving dose limiting toxicity that has not progressed to evaluation in later line studies. We have previously shown that high dose AAP selectively depletes glutathione in the liver but not the tumor, suggesting that NAC, the FDA-approved antidote for AAP toxicity and a glutathione precursor, may selectively rescue the normal liver but not the tumor from high dose AAP. While the anti-tumor effects of AAP/NAC appear to not be mediated by glutathione depletion and free radical injury, the mechanism of anti-tumor effects of AAP/NAC has not been definitively characterized. Methods: In vitro the effects of Vehicle, AAP, or AAP/NAC was evaluated on bone marrow derived macrophages polarized to M2 and M1 phenotypes using IL-4 or IFN/LPS, respectively. Tumor cell viability was assessed with MTT assay. Effects of AAP on IL-4/STAT6 (M2) or IFN/LPS/STAT1 (M1) signaling, and downstream gene and protein expression was studied. In vivo, effects of AAP/NAC on tumor size and tumor associated macrophage polarization were characterized in orthotopic triple negative breast tumor models 4T1 and EF43.fgf4 using cytokine elisa of tumor lysate and flow cytometry. Results: NAC reversed AAP toxicity in the normal liver but did not reverse AAP cytotoxicity against tumor cells in vitro. AAP/NAC selectively inhibited IL-4-induced STAT6 phosphorylation but not IFN/LPS-induced STAT1 phosphorylation. Downstream, AAP/NAC inhibited IL-4 induction of M2-associated genes (such as CCL24, YM1 and arginase) and proteins (arginase, PD-L2, and CD206). However, AAP/NAC did not inhibit IFN/LPS induction of M1-associated genes (IL-6, TNF, IL-12) and proteins (INOS, PD-L1, MHC I, and CD64). In vivo, AAP/NAC inhibited tumor growth in EF43.fgf4 and 4T1 triple negative breast tumors. Flow cytometry of tumor associated macrophages revealed that AAP/NAC selectively inhibited M2 but not M1 polarization. ELISA of tumor lysate demonstrated relatively stable expression of IFN gamma but markedly suppressed expression of IL-10 in the tumor immune microenvironment. Conclusion: Our study is the first to show that at high doses AAP/NAC has profound effects on the tumor immune microenvironment that may facilitate immune-mediated inhibition of tumor growth. Citation Format: Alexander Neuwelt, Allyn Bryan, Won Lee, Pavani Pingali, Howard Li, Bhaumik Patel. High dose acetaminophen with n-acetylcysteine rescue inhibits M2 polarization of tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6388.
Abstract 5004: DDR-targeting small molecule inhibitor as a novel therapeutic for treating pancreatic ductal adenocarcinoma
Authors: Trong Phat Do, Sajid Khan, Daohong Zhou, Matthew Hart, Stanton McHardy, Manjeet Rao
Journal: Cancer Research (2023)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the second most significant cause of cancer-related mortality, with a 5-year survival rate of just 11%. PDACs are one of the most difficult to treat cancers, mainly because of the desmoplastic tumor microenvironment enriched with tumor-supportive extracellular matrix (ECM) and stromal cells. Unfortunately, the efficacies of current pancreatic cancer therapies are limited partly by stroma-mediated drug resistance. We reason that Discoidin Domain Receptors, which belong to the receptor tyrosine kinase family and bind to fibrillar collagens present in the ECM, may be a critical promoter of PDAC growth and progression. Though several drugs targeting DDR proteins have been developed, no inhibitors specific to DDR proteins have been developed. Moreover, those drugs have not been approved for treating PDACs. Methods. A high throughput screen using small molecule inhibitors was performed to identify bonafide inhibitors of DDR proteins. Structural and reported-based essays were done to determine the specificity. Functional assays were performed to test the potency of the candidate inhibitors. Mechanistic studies were done using RNA-seq, real-time PCR, and western blot. Results: Using an unbiased screening approach, we identified inhibitors that specifically target DDR proteins. Our studies revealed that small molecule inhibitors blocked the short and long-term viability as well as migration/invasion of PDAC cells. In addition, they induced apoptosis and halted the cell cycle at the G1-S checkpoint. Mechanistic studies revealed that the pro-growth signaling cascade was significantly inhibited. Conclusions: Our results showing specific DDR inhibitors blocking the growth and progression of PDAC cells without affecting the viability of normal cells suggest that these inhibitors may serve as a safe and potent regimen for treating pancreatic cancers. Citation Format: Trong Phat Do, Sajid Khan, Daohong Zhou, Matthew Hart, Stanton McHardy, Manjeet Rao. DDR-targeting small molecule inhibitor as a novel therapeutic for treating pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5004.
Abstract 2229: Cell state transitions shape the intratumoral composition of small cell lung carcinoma
Authors: Priyanka Gopal, Aaron Petty, Kevin Rogacki, Titas Bera, Rohan Bareja, Craig Peacock, Mohamed Abazeed
Journal: Cancer Research (2023)

Abstract Introduction: Small cell lung carcinoma (SCLC) is characterized by rapid growth, early metastases, and initial response followed by almost invariable resistance to therapy. Studies to date have not determined the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. We sought to characterize the intra-tumoral transcriptional heterogeneity of SCLC. We identify multivalent, distinct, and commutable transcriptional states that confer discrete functions in individual SCLC tumors. Methods: We developed a biorepository of patient-derived xenografts (PDX) (n = 64) and matched PDX-derived ex vivo lines. We used multi-omic profiling (RNAseq, scRNAseq, and ATAC seq), single-cell fluorescence tracking of fate-defining transcription factor (TF)-driven states, and mathematical and statistical models (Markov chain) to study the topology of the SCLC transcriptional landscape and its plasticity. Human tumor material and associated clinical data were obtained after informed written consent on an IRB-approved prospective registry. Results: We show that individual SCLC tumors are more heterogenous than previously appreciated, displaying distinctive equilibria in the proportion of cells within well-delimited cellular states (ASCL1, NEUROD1 and YAP1). We also show that transcriptional states undergo transitions, which we identified as a mechanism for maintaining cell state diversity. We measured the kinetics of state transitions using single-cell fluorescence tracking of ex vivo cultures and found that these measure were associated significantly with transition estimates using stochastic transition theory (i.e. Markov chains). ATAC-seq profiling indicated a role for the epigenome in the state diversity of SCLC. Namely, there was preferential promoter accessibility to Ascl1, NeuroD1, and Yap1 in a manner consistent with gene and protein expression in the respective subpopulations. Our results indicate that the transition rates between cell types in individual tumors were largely governed by tendencies to reach an equilibrium state that are critical for configuring intratumoral cell state proportions. Conclusion: In conclusion, we demonstrate that TF driven cell states can transition to maintain an equilibrium in cell state proportions. Our work advances a model of cellular states and program diversity in SCLC and nominates new therapeutic strategies designed to limit the plasticity of this lethal cancer. Citation Format: Priyanka Gopal, Aaron Petty, Kevin Rogacki, Titas Bera, Rohan Bareja, Craig Peacock, Mohamed Abazeed. Cell state transitions shape the intratumoral composition of small cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2229.
Rates of Menstrual History-Taking and Counseling With Anticancer Treatments Are Low: People Who Menstruate Deserve Gender-Specific Cancer Care
Authors: Verity Chadwick, Michaela Kim, Georgia Mills, Catherine Tang, Antoinette Anazodo, Rachel Dear, Rachael Rodgers, Orly Lavee, Samuel Milliken, Georgia McCaughan, John Moore, Barbara Withers, Nada Hamad
Journal: Journal of the National Comprehensive Cancer Network (2023)

Chemotherapy predisposes people who menstruate to abnormal uterine bleeding that can be life-threatening and may also damage ovaries, resulting in premature menopause. The purpose of this study was to explore the incidence of menstrual history documentation and counseling before, during, and after cancer treatment.The medical charts of 137 consecutive females (self-reported) aged 18 to 49 years receiving anticancer treatment at a major tertiary metropolitan hospital in Australia between 2017 and 2020 were reviewed. Data collected included primary diagnosis, stage of cancer, treatment(s) received, rates of remission or progression, documentation of involvement of a specialist gynecologist, reproductive history, menstrual disturbances, menstruation counseling or intervention offered, and diagnosis of early ovarian failure.Only 16.1% of patients had their menstrual history documented at the initial consult, and 49.6% had their menstrual history documented at a subsequent consult with their treating oncologist or hematologist. Most (82.4%) patients with a menstrual history documented experienced menstrual disturbance posttreatment, most commonly amenorrhea (48.0%), followed by menopause or menopause symptoms (20.6%), irregular menstrual bleeding (16.7%), menorrhagia (13.7%), dysmenorrhea (3.9%), and iron deficiency from bleeding (2.9%). Menopause/Menopausal symptoms and iron deficiency were more likely to be treated than other disturbances.Menstruation disturbance is a common side effect of cancer treatment. Menstrual care should be integral to cancer care for people who menstruate, and higher engagement could be achieved through education of medical and allied health staff, information technology systems automating prompts and referral pathways, regular audits to ensure compliance, better alliances between cancer and fertility specialists, and the creation of accessible patient information to promote awareness and facilitate discussion.
NCCN News
Authors: Robert Carlson
Journal: Journal of the National Comprehensive Cancer Network (2023)

NCCN Announced Collaboration With Cancer Experts in PolandNCCN has announced a new collaboration with the Institute of Hematology and Transfusion Medicine in Poland (IHiT), and the Alliance For Innovation-Polish American Foundation (AFI) on February 27, 2023.The 3 organizations have signed an agreement enabling clinicians to share their established expertise and international experience in order to improve quality of care and outcomes for patients with hematologic malignancies in Poland and around the world.
Association Between Pretreatment Skeletal Muscle and Outcomes After CAR T-Cell Therapy
Authors: Kyuwan Lee, Aleksi Iukuridze, Tianhui He, Alysia Bosworth, Lanie Lindenfeld, Jennifer Berano Teh, Meagan Echevarria, Sophia Albanese, Liezl Atencio, Rusha Bhandari, F. Lennie Wong, Andrew S. Artz, Tanya Siddiqi, Liana Nikolaenko, Jasmine Zain, Matthew Mei, Geoffrey Shouse, Leslie L. Popplewell, Alex F. Herrera, L. Elizabeth Budde, Stephen J. Forman, Saro H. Armenian
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: The purpose of this study was to examine the association between baseline skeletal muscle measurements, acute toxicity (immune effector cell–associated neurotoxicity syndrome [ICANS], cytokine release syndrome), and treatment efficacy in patients undergoing CAR T-cell therapy for B-lineage lymphoma. Patients and Methods: Skeletal muscle measurements were obtained from automated CT measurements in 226 consecutive patients who received CAR T-cell therapy between 2015 and 2021. The Kaplan-Meier method was used to examine progression-free survival (PFS) and overall survival (OS) at 1-year. Multivariable regression was used to calculate the hazard ratio (HR) with 95% confidence intervals, adjusted for covariates. Results: The median age of the cohort was 63.1 years (range, 18.5–82.4 years), and most patients were male (66%) and had primary refractory disease (58%). Patients with abnormally low skeletal muscle at baseline were at greater risk of ICANS (HR, 1.74; 95% CI, 1.05–2.87) and had longer length of hospitalization (mean 27.7 vs 22.9 days; P &lt;.05) compared with those with normal muscle mass. Abnormal skeletal muscle was independently associated with risk of disease progression (HR, 1.70; 95% CI, 1.11–2.57) and worse survival (HR, 2.44; 95% CI, 1.49–4.00) at 1 year compared with normal skeletal muscle. Individuals who had abnormal skeletal muscle and high lactate dehydrogenase (LDH) levels at baseline had poor 1-year PFS (17%) and OS (12%) compared with those with normal skeletal muscle and LDH levels (72% and 82%, respectively; P &lt;.001). Patients who had abnormal skeletal muscle and LDH levels had a 5-fold risk (HR, 5.34; 95% CI, 2.97–9.62) of disease progression and a 10-fold risk (HR, 9.73; 95% CI, 4.81–19.70) of death (reference: normal skeletal muscle, normal LDH), independent of prior lines of therapy, extent of residual disease at time of CAR T-cell therapy, functional status, or product. Conclusions: This information can be used for risk stratification prior to CAR T-cell therapy or to implement prehabilitation and nutritional optimization before lymphodepletion as well as thereafter. These efforts will be complementary to ongoing efforts toward sustained efficacy after CAR T-cell therapy.
HER2 Targeting in Esophagogastric Cancer: Redefining the Landscape and Breaking Barriers
Authors: Samuel L. Cytryn, Yelena Y. Janjigian
Journal: Journal of the National Comprehensive Cancer Network (2023)

HER2 is overexpressed in approximately 20% of esophagogastric cancer (EGC) cases. The addition of the anti-HER2 antibody, trastuzumab, to chemotherapy in 2010 was the first targeted treatment to demonstrate an improvement in survival. The aggressive nature and heterogeneous biology of EGC have posed a particular challenge and resulted in numerous negative trials without a change in standard of care for more than a decade. However, with the incorporation of dual HER2 and PD-1 blockade as well as the advent of a new, potent antibody–drug conjugate, trastuzumab deruxtecan, there have been 2 new FDA approvals for this patient population within the past 2 years. Consequently, the management and landscape of HER2-positive EGC is rapidly changing and increasingly optimistic.
Primary Palliative Care Improves Uptake of Advance Care Planning Among Patients With Advanced Cancers
Authors: Michael G. Cohen, Andrew D. Althouse, Robert M. Arnold, Douglas White, Edward Chu, Margaret Rosenzweig, Kenneth J. Smith, Yael Schenker
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: Palliative care specialists are experts in conducting advance care planning (ACP) but are a limited resource. Oncology nurses often have special relationships with their patients and thus may be poised to provide primary palliative care. We sought to determine the impact of a nurse-led primary palliative care intervention on ACP uptake among patients with advanced cancer. Methods: We performed a secondary analysis of a cluster randomized controlled trial examining the impact of nurse-based primary palliative care. In the parent trial, patients with advanced cancer received either monthly primary palliative care visits with trained nurses within their cancer center or standard care. Nurses in the intervention arm received special training in ACP. ACP uptake was assessed at enrollment and 3 months later evaluating (1) whether an end-of-life conversation (EOLC) occurred with one’s oncologist, and (2) completion of an advance directive (AD). Multivariable logistic regression tested differences in ACP uptake by treatment arm adjusted for age, religious importance, education, time with current oncologist, and performance status. Results: Of 672 patients enrolled, 182/336 (54%) patients in the intervention arm and 196/336 (58%) in the standard care arm lacked an EOLC at baseline and completed the 3-month assessment. Of those, 82/182 (45.1%) patients in the intervention arm and 29/196 (14.8%) in the standard care arm reported having an EOLC at 3 months (adjusted odds ratio, 5.28; 95% CI, 3.10–8.97; P &lt;.001). Similarly, 111/336 (33%) patients in the intervention arm and 105/336 (31%) in the standard care arm lacked an AD at baseline and completed the 3-month assessment. Of those, 48/111 (43.2%) patients in the intervention arm and 19/105 (18.1%) in the standard care arm completed an AD over the study period (adjusted odds ratio, 3.68; 95% CI, 1.89–7.16; P &lt;.001). Conclusions: Nurse-led primary palliative care increased ACP uptake among patients with advanced cancer. Training oncology nurses embedded within community cancer centers to provide primary palliative care may help improve ACP access.
Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents
Authors: Lucas Moreno, Steven G. DuBois, Julia Glade Bender, Audrey Mauguen, Nick Bird, Vickie Buenger, Michela Casanova, François Doz, Elizabeth Fox, Lia Gore, Douglas S. Hawkins, Shai Izraeli, David T.W. Jones, Pamela R. Kearns, Jan J. Molenaar, Karsten Nysom, Stefan Pfister, Gregory Reaman, Malcolm Smith, Brenda Weigel, Gilles Vassal, Christian Michel Zwaan, Xavier Paoletti, Alexia Iasonos, Andrew D.J. Pearson
Journal: Journal of Clinical Oncology (2023)

There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders.